Circadian rhythms are an integral component of life, structuring temporal patterns of biochemistry, physiology and behavior. These cycles are driven by an internal biological clock with an endogenous <24 hr period. The master circadian pacemaker is located in the mammalian hypothalamic suprachiasmatic nucleus (SCN). Disorders of the circadian timing system have been linked to a mental illness and metabolic disorders and understanding the neurobiology and physiology of circadian rhythms should lead to the development of new medical treatments. We propose to study the role of Inhibitor of DNA-binding (Id) genes as potential modulators of the mammalian circadian system. Our preliminary studies reveal that Id genes are rhythmically expressed within the SCN and peripheral tissues; that Id2 null mice show circadian disorder phenotypes, including an enhanced speed of reentrainment of the clock following a large time-zone transition; the ability for ID proteins to inhibit the activity of known clock components; and that a subset of normal circadian outputs in the liver are disrupted in Id2 null mice. Our proposed research will focus on 1) characterizing the protein-protein interaction between ID2 and canonical clock proteins CLOCK, BMAL1 and other relevant bHLH transcription factors; 2) define the molecular basis for the described phenotypes, utilizing both traditional methods of gene and protein expression visualization, and real-time analysis of gene/protein expression using the mPER2-LUCIFERASE mouse system; and 3) examine the role of ID2 in regulating transcriptional pathways of clock output, focusing upon mouse hepatic and metabolic systems. It is expected that these collective studies will provide a greater understanding of the role of Id genes in the molecular clockwork of the mammalian central and peripheral circadian clocks. PUBLIC HEALTH RELEVANCE: Disorders of the circadian timing system have been linked to mental illness, such as depression and sleep disorders, and metabolic disorders, and understanding the neurobiology, physiology and molecular basis of circadian rhythms should lead to the development of new treatments. We propose to study the role of Inhibitor of DNA-binding (Id) genes as components of the mammalian circadian system. It is expected that these collective studies will provide greater understanding of the role of ID transcriptional regulators in the molecular clockwork of the mammalian central and peripheral circadian clocks.